Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][C:7]([NH:11][C:12]([C:14]3[C:15]([C:20]4[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=4)=[CH:16][CH:17]=[CH:18][CH:19]=3)=[O:13])=[CH:8][CH:9]=2)[CH2:4][CH2:3][NH:2]1.Br[CH2:31][C:32]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=O.C(=O)([O-])[O-:41].[K+].[K+]>C(#N)C>[O:41]=[C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:34]1[CH2:32][CH2:31][N:2]1[CH2:3][CH2:4][C:5]2[C:10](=[CH:9][CH:8]=[C:7]([NH:11][C:12]([C:14]3[C:15]([C:20]4[CH:25]=[CH:24][C:23]([C:26]([F:27])([F:28])[F:29])=[CH:22][CH:21]=4)=[CH:16][CH:17]=[CH:18][CH:19]=3)=[O:13])[CH:6]=2)[CH2:1]1
Reactant: O=C(CBr)c1ccccc1
Reactant: O=C(Nc1ccc2c(c1)CCNC2)c1ccccc1-c1ccc(C(F)(F)F)cc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=C(Nc1ccc2c(c1)CCN(CCC1C=CC=CC1=O)C2)c1ccccc1-c1ccc(C(F)(F)F)cc1

Procedure:
Compound (II) (0.30 gm, 0.76 mmole), 2-bromoacetophenone (0.15 g, 0.76 mmole) and potassium carbonate (0.12 gm, 0.83 mmole) were combined in 20 mL of acetonitrile and heated to reflux for 1 hr., and then the solvent was evaporated under vacuum. The residue was dissolved in chloroform and washed with saturated sodium bicarbonate. Purification of the dried organic layer was accomplished with silica gel chromatography using 50% ethyl acetate in hexane as the eluent.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[C@H:9]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]([F:17])[CH:11]=2)[O:8][CH2:7][CH2:6][N:5]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:4]1.[CH2:25]([O:27][CH2:28][C:29](O)=[O:30])[CH3:26].N1(O)C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>C1COCC1.C(N(CC)CC)C>[Cl:16][C:13]1[CH:14]=[CH:15][C:10]([C@@H:9]2[O:8][CH2:7][CH2:6][N:5]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:4][C@H:3]2[CH2:2][NH:1][C:29](=[O:30])[CH2:28][O:27][CH2:25][CH3:26])=[CH:11][C:12]=1[F:17]
Reactant: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(Cl)c(F)c2)[C@H](CN)C1
Reactant: CCOCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOCC(=O)NC[C@@H]1CN(C(=O)OC(C)(C)C)CCO[C@H]1c1ccc(Cl)c(F)c1
Reaction time: 8 h
Yield: 83.6 %

Procedure:
To a solution of tert-butyl (6R,7R)-6-(aminomethyl)-7-(4-chloro-3-fluorophenyl)-1,4-oxazepane-4-carboxylate (150 mg), ethoxyacetic acid (35 mg), 1H-benzotriazol-1-ol (67.8 mg) and triethylamine (0.146 ml) in THF (2.1 mL) was added N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (96 mg), and the mixture was stirred overnight. To the reaction mixture was added distilled water, and the mixture was extracted with ethyl acetate. The extract was washed with distilled water and brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (hexane/ethyl acetate) to give the title compound (125 mg).
Reaction SMILES: Br[C:2]1([C:11]2[CH:16]=[CH:15][C:14]([O:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:13][CH:12]=2)[C:7](=[O:8])[NH:6][C:5](=[O:9])[NH:4][C:3]1=[O:10].[OH:24][CH2:25][CH2:26][N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1>CO>[O:17]([C:14]1[CH:15]=[CH:16][C:11]([C:2]2([CH:28]3[CH2:29][NH:30][CH2:31][CH2:32][N:27]3[CH2:26][CH2:25][OH:24])[C:7](=[O:8])[NH:6][C:5](=[O:9])[NH:4][C:3]2=[O:10])=[CH:12][CH:13]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: OCCN1CCNCC1
Reactant: O=C1NC(=O)C(Br)(c2ccc(Oc3ccccc3)cc2)C(=O)N1
Solvent: CO
Product: O=C1NC(=O)C(c2ccc(Oc3ccccc3)cc2)(C2CNCCN2CCO)C(=O)N1
Reaction time: 2 h
Yield: 75.3 %

Procedure:
A solution of 5-bromo-5-(4'-phenoxyphenyl)barbituric acid (50 mg) in 0.2 ml of methanol is added dropwise with a solution of N-(2-hydroxyethyl)piperazine (52 mg) in 0.6 ml of methanol and the mixture is stirred for 2 hours. The white precipitate is recovered by filtration and dried under vacuum at 60° C. overnight. 42.6 mg of the product are obtained, m.p. >240° C.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.C([N:10]([CH2:13][CH3:14])[CH2:11][CH3:12])C.[CH3:15][OH:16]>>[N:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[N:10]1[CH2:11][CH2:12][CH:15]([OH:16])[CH2:14][CH2:13]1
Reactant: CCN(CC)CC
Reactant: Fc1ccccn1
Reactant: CO
Product: OC1CCN(c2ccccn2)CC1
Yield: 64.7 %

Procedure:
1-(pyridin-2-yl)piperidin-4-ol (64.7% yield), 2-fluoropyridine (29.7 mmol, 2.88 g) and triethylamine (49.4 mmol, 6.89 ml, 5.00 g) were dissolved in MeOH (2.5 ml) and heated to 150° C. for 1 hour in the microwave. The solvent was removed at reduced pressure. The resulting residue was purified by column chromatography, eluting with DCM—3% MeOH/DCM to afford 1-(pyridin-2-yl)piperidin-4-ol. (1.14 g) 1H NMR (CDCl3) δ: 8.18 (d, 1H), 7.45 (m, 1H), 6.67 (d, 1H), 6.58 (m, 1H), 4.06 (m, 2H), 3.92 (br, 1H), 3.15 (m, 2H), 1.98 (m, 2H), 1.59 (m, 2H).
Reaction SMILES: [CH2:1]([C:8]1([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.[Br:28][C:29]1[CH:30]=[N:31][C:32](Cl)=[N:33][CH:34]=1.CCCCCC>CCO>[CH2:1]([C:8]1([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:9][CH2:10][N:11]([C:32]2[N:33]=[CH:34][C:29]([Br:28])=[CH:30][N:31]=2)[CH2:12][CH2:13]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Clc1ncc(Br)cn1
Reactant: CCOC(=O)C1(Cc2ccccc2)CCNCC1
Solvent: CCCCCC
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C1(Cc2ccccc2)CCN(c2ncc(Br)cn2)CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 17.2 %

Procedure:
To a solution of ethyl 4-benzylpiperidine-4-carboxylate (0.46 g, 1.86 mmol) in EtOH (10.0 mL) was added DIPEA (0.80 mL, 4.65 mmol) at rt which was stirred at rt for 10 minutes followed by addition of 5-bromo-2-chloropyrimidine (0.30 g, 1.55 mmol). The reaction was heated up to 70° C. for 1 h. After completion of reaction (by TLC), solvent was evaporated and the crude residue purified over 100-200 M silica-gel using 4% EtOAc:hexane to obtain the desired product as a yellow solid (0.108 g, 45% yield). 1H NMR (DMSO-d6): δ 1.16 (t, J=7.20 Hz, 3H), 1.47 (m, 2H), 2.00 (m, 2H), 2.80 (s, 2H), 2.97 (m, 2H), 4.08 (q, J=7.20 Hz, 2H), 4.40 (m, 2H), 7.02 to 7.27 (m, 5H) and 8.43 (s, 2H).
Reaction SMILES: C(O)(=O)C.[CH:5]1([O:11][N:12]2[C:17]([CH3:19])([CH3:18])[CH2:16][C:15](=O)[CH2:14][C:13]2([CH3:22])[CH3:21])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1.[CH2:23]([NH2:35])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34].C([BH3-])#N.[Na+]>O1CCCC1>[CH:5]1([O:11][N:12]2[C:17]([CH3:19])([CH3:18])[CH2:16][CH:15]([NH:35][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])[CH2:14][C:13]2([CH3:22])[CH3:21])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1
Reactant: CCCCCCCCCCCCN
Reactant: CC1(C)CC(=O)CC(C)(C)N1OC1CCCCC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CCCCCCCCCCCCNC1CC(C)(C)N(OC2CCCCC2)C(C)(C)C1
Temperature: 21 °C
Reaction time: 4 h
Yield: 81.5 %

Procedure:
Acetic acid (22.0 g, 367 mmol) is added dropwise to a solution of 15.0 g (59.2 mmol) of 1-cyclohexyloxy-2,2,6,6-tetramethylpiperidin-4-one and 54.9 g (296 mmol) of dodecylamine in 200 ml of dry tetrahydrofuran containing 5A molecular sieves (25 g). The reaction mixture warms during the addition. The mixture is then diluted with tetrahydrofuran (150 ml) and cooled to 21° C. Sodium cyanoborohydride (4.46 g, 7.1 mmol) is added in one portion. The reaction mixture is stirred at room temperature for 4 hours, then filtered. The filtrate is concentrated and the residue is partitioned between ether (400 ml) and 5% sodium hydroxide (250 ml). The organic layer is dried over magnesium sulfate, filtered, and concentrated. Residual dodecylamine is removed by Kugelrohr distillation (110° C., 0.3 mm). The crude product is purified by chromatography (silica gel) to afford 20.4 g (82% yield) of the title compound, as a nearly colorless oil.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][C:23]=1[O:24][CH3:25])[C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([N:14]2[CH2:19][CH2:18][N:17]([CH3:20])[CH2:16][CH2:15]2)=[CH:10][CH:9]=1)=[O:6].C([O:28][C:29]([C:31]1[CH:36]=[CH:35][C:34](B(O)O)=[CH:33][CH:32]=1)=[O:30])C.COCCOC.C(=O)([O-])[O-].[Cs+].[Cs+]>O>[CH3:25][O:24][C:23]1[CH:22]=[CH:21][C:4]([C:5](=[O:6])[NH:7][C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH2:19][CH2:18][N:17]([CH3:20])[CH2:16][CH2:15]3)=[CH:10][CH:9]=2)=[CH:3][C:2]=1[C:34]1[CH:35]=[CH:36][C:31]([C:29]([OH:30])=[O:28])=[CH:32][CH:33]=1
Reactant: CCOC(=O)c1ccc(B(O)O)cc1
Reactant: COc1ccc(C(=O)Nc2ccc(N3CCN(C)CC3)cc2)cc1Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: COCCOC
Product: COc1ccc(C(=O)Nc2ccc(N3CCN(C)CC3)cc2)cc1-c1ccc(C(=O)O)cc1
Reaction time: 16 h

Procedure:
A mixture of 3-Bromo-4-methoxy-N-[4-(4-methyl-piperazin-1-yl)-phenyl]-benzamide (748 mg) and 4-(ethoxycarbonyl)-phenyl boronic acid (538 mg) in 2:1 DME:water (15 ml) containing cesium carbonate (1.21 mg) and tetrakis(triphenylphosphine)palladium0 (220 mg) was heated to reflux for 18 h. The mixture was cooled and then evaporated. The residue was then stirred in ethanol (8 ml) and 2M NaOH (4 ml) at room temp for 16 h. The ethanol was then evaporated and the residue acidified with 2M HCl. The resulting solid was collected by filtration and dried (528 mg)
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[CH:6][CH:5]=1)([O-:3])=[O:2].[NH2:11][C:12]1[N:17]=[C:16](Cl)[CH:15]=[C:14]([CH3:19])[N:13]=1.Cl>C(OCCO)C>[CH3:19][C:14]1[N:13]=[C:12]([NH2:11])[N:17]=[C:16]([NH:8][C:7]2[CH:9]=[CH:10][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)[CH:15]=1
Reactant: Cc1cc(Cl)nc(N)n1
Reactant: Nc1ccc([N+](=O)[O-])cc1
Agent: Cl
Solvent: CCOCCO
Product: Cc1cc(Nc2ccc([N+](=O)[O-])cc2)nc(N)n1
Temperature: 25 °C
Yield: 42.7 %

Procedure:
4-Nitroaniline (B1) [9.22 g, 0.07 mol] and 2-amino-4-chloro-6-methylpyrimidine (E1) (9.30 g, 0.07 mol) were dissolved in 2-ethoxyethanol (330 mL). To the resulting solution were added a few drops of c.HCl, and the resulting mixture was refluxed for 30 min, and then allowed to cool to room temperature overnight. After this time, the reaction mixture was filtered, and the resulting solid was basified by addition of aqueous ammonia solution, and then crystallized from H2O:EtOH to afford amine E2 as an amorphous bright-yellow solid (7.33 g). Concentration of the filtrate, followed by basification and reprecipitation as before, afforded a further quantity (0.78 g, overall yield 51%). 1H NMR [(CD3)2SO]: 2.14 [s, 3H, ArCH3], 6.00 [s, 1H, ArNHAr], 6.37 [s, 2H, ArNH2], 8.00 [ddd, J=10.24, 5.05, 2.96 Hz, 2H, ArH], 8.12 [ddd, J=10.24, 4.95, 2.90 Hz, 2H, ArH], 9.75 [s, 1H, ArH]. LCMS (APCI+): 246 (100%).
Reaction SMILES: [OH-:1].[Na+].[CH3:3][N:4]1[CH:8]=[C:7]([C:9]#N)[C:6]([N+:11]([O-:13])=[O:12])=[N:5]1.Cl.[OH2:15]>>[CH3:3][N:4]1[CH:8]=[C:7]([C:9]([OH:15])=[O:1])[C:6]([N+:11]([O-:13])=[O:12])=[N:5]1
Reactant: Cn1cc(C#N)c([N+](=O)[O-])n1
Reactant: O
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Product: Cn1cc(C(=O)O)c([N+](=O)[O-])n1

Procedure:
A solution was made of 350 ml. of water, 35 gm. of NaOH, and 32 gm. of 1-methyl-3-nitro-4-pyrazolecarbonitrile. The solution was refluxed for 18 hours, cooled in an ice bath, and then acidified to pH 2 with concentrated HCl. A solid precipitated, which was filtered, washed with cold water, and recrystallized from methanol-water. The yield was 32.5 gm. of 1-methyl-3-nitro-4-pyrazolecarboxylic acid, m.p. 185°-187° C.
Reaction SMILES: [CH3:1][S:2]([N:5]1[CH2:10][CH2:9][CH2:8][C@H:7]([NH:11][C:12]2[C:17]([C:18]3[N:19]=[C:20]4[CH:26]=[CH:25][N:24](COCC[Si](C)(C)C)[C:21]4=[N:22][CH:23]=3)=[CH:16][N:15]=[C:14](S(C)(=O)=O)[N:13]=2)[CH2:6]1)(=[O:4])=[O:3].[CH2:39]([NH2:42])[CH2:40][NH2:41].CS(C)(=O)=O>O1CCOCC1>[NH2:41][CH2:40][CH2:39][NH:42][C:14]1[N:13]=[C:12]([NH:11][C@H:7]2[CH2:8][CH2:9][CH2:10][N:5]([S:2]([CH3:1])(=[O:4])=[O:3])[CH2:6]2)[C:17]([C:18]2[N:19]=[C:20]3[CH:26]=[CH:25][NH:24][C:21]3=[N:22][CH:23]=2)=[CH:16][N:15]=1
Reactant: C[Si](C)(C)CCOCn1ccc2nc(-c3cnc(S(C)(=O)=O)nc3N[C@H]3CCCN(S(C)(=O)=O)C3)cnc21
Reactant: NCCN
Agent: CS(C)(=O)=O
Solvent: C1COCCO1
Product: CS(=O)(=O)N1CCC[C@H](Nc2nc(NCCN)ncc2-c2cnc3[nH]ccc3n2)C1

Procedure:
In a dioxane solution of ((S)-1-methanesulfonyl-piperidin-3-yl)-{2-methanesulfonyl-5-[5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl]-pyrimidin-4-yl}-amine derived from Example 84, step 1, ethylenediamine was used to displace the methylsulfone similar to examples above and the de-protection step was similar to step 5, Example 76, to give N*2*-(2-amino-ethyl)-N*4*-((S)-1-methanesulfonyl-piperidin-3-yl)-5-(5H-pyrrolo[2,3-b]pyrazin-2-yl)-pyrimidine-2,4-diamine. MS: (ES+): 432.
Reaction SMILES: [CH3:1][C@H:2]([NH:5][C:6](=[O:15])[O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH:3]=[O:4].[CH2:16]([Mg]Br)[CH:17]=[CH2:18].O>O1CCCC1>[OH:4][CH:3]([CH2:18][CH:17]=[CH2:16])[C@@H:2]([NH:5][C:6](=[O:15])[O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH3:1]
Reactant: C[C@@H](C=O)NC(=O)OCc1ccccc1
Reactant: C=CC[Mg]Br
Solvent: O
Solvent: C1CCOC1
Product: C=CCC(O)[C@H](C)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution (30 mL) of benzyl [(1S)-1-methyl-2-oxoethyl]carbamate (3.0 g) in tetrahydrofuran was added 1.0 mol/L solution (28.8 mL) of allylmagnesium bromide in tetrahydrofuran under ice-cooling, and the mixture was stirred at room temperature for 18 hr. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (developing solvent: hexane:ethyl acetate=9:1→1:1) to give benzyl [(1S)-2-hydroxy-1-methylpent-4-en-1-yl]carbamate as a colorless oil. To a solution (10 mL) of the obtained benzyl [(1S)-2-hydroxy-1-methylpent-4-en-1-yl]carbamate in tetrahydrofuran were added 2,6-lutidine (0.629 mL) and tert-butyldimethylsilane trifluoromethanesulfonate (0.91 mL) and the mixture was stirred at room temperature for 30 min. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The extract was washed with 1 mol/L hydrochloric acid, saturated aqueous sodium hydrogencarbonate solution and saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (developing solvent: hexane:ethyl acetate=9:1→2:1) to give the title compound as a colorless oil (yield: 610 mg).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:29])[CH2:5][S:6][C:7]1[S:11][C:10]([NH:12][C:13]([N:15]([C@H:22]2[CH2:27][CH2:26][C@H:25]([CH3:28])[CH2:24][CH2:23]2)[CH:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)=[O:14])=[N:9][CH:8]=1)[CH3:2].[N:30]1([C:36](Cl)=[O:37])[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1>>[CH2:1]([O:3][C:4](=[O:29])[CH2:5][S:6][C:7]1[S:11][C:10]([NH:12][C:13]([N:15]([C@H:22]2[CH2:23][CH2:24][C@H:25]([CH3:28])[CH2:26][CH2:27]2)[CH:16]2[CH2:21][CH2:20][N:19]([C:36]([N:30]3[CH2:35][CH2:34][O:33][CH2:32][CH2:31]3)=[O:37])[CH2:18][CH2:17]2)=[O:14])=[N:9][CH:8]=1)[CH3:2].[CH3:28][C@H:25]1[CH2:26][CH2:27][C@H:22]([N:15]([CH:16]2[CH2:17][CH2:18][N:19]([C:36]([N:30]3[CH2:35][CH2:34][O:33][CH2:32][CH2:31]3)=[O:37])[CH2:20][CH2:21]2)[C:13](=[O:14])[NH:12][C:10]2[S:11][C:7]([S:6][CH2:5][C:4]([OH:3])=[O:29])=[CH:8][N:9]=2)[CH2:23][CH2:24]1
Reactant: O=C(Cl)N1CCOCC1
Reactant: CCOC(=O)CSc1cnc(NC(=O)N(C2CCNCC2)[C@H]2CC[C@H](C)CC2)s1
Product: CCOC(=O)CSc1cnc(NC(=O)N(C2CCN(C(=O)N3CCOCC3)CC2)[C@H]2CC[C@H](C)CC2)s1
Product: C[C@H]1CC[C@H](N(C(=O)Nc2ncc(SCC(=O)O)s2)C2CCN(C(=O)N3CCOCC3)CC2)CC1

Procedure:
(2-{3-(trans-4-Methyl-cyclohexyl)-3-[1-(morpholine-4-carbonyl)-piperidin-4-yl]-ureido}-thiazol-5-ylsulfanyl)-acetic acid ethyl ester was prepared in a similar manner to Example 554 using {2-[3-(trans-4-methyl-cyclohexyl)-3-piperidin-4-yl-ureido]-thiazol-5-ylsulfanyl}-acetic acid ethyl ester and 4-morpholinecarbonyl chloride. Hydrolysis using general procedure (F) gave the title compound HPLC-MS: m/z 526 (M+).
Reaction SMILES: Br[C:2]1[S:22][C:5]2=[N:6][C:7]([CH3:21])=[CH:8][C:9]([NH:10][S:11]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[CH:15]=3)(=[O:13])=[O:12])=[C:4]2[C:3]=1[CH3:23].[CH:24]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:27](B(O)O)=[CH:26][N:25]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:20][C:16]1[CH:15]=[C:14]([S:11]([NH:10][C:9]2[CH:8]=[C:7]([CH3:21])[N:6]=[C:5]3[S:22][C:2]([C:27]4[C:28]5[C:33](=[CH:32][CH:31]=[CH:30][CH:29]=5)[CH:24]=[N:25][CH:26]=4)=[C:3]([CH3:23])[C:4]=23)(=[O:13])=[O:12])[CH:19]=[CH:18][CH:17]=1
Reactant: OB(O)c1cncc2ccccc12
Reactant: Cc1cc(NS(=O)(=O)c2cccc(Cl)c2)c2c(C)c(Br)sc2n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: Cc1cc(NS(=O)(=O)c2cccc(Cl)c2)c2c(C)c(-c3cncc4ccccc34)sc2n1
Temperature: 100 °C
Yield: 37.2 %

Procedure:
To a solution of N-(2-bromo-3,6-dimethylthieno[2,3-b]pyridin-4-yl)-3-chlorobenzenesulfonamide (Example 77) (100 mg, 0.232 mmol) in 1,4-dioxane (2 mL) and water (1 mL) was added 4-isoquinolinylboronic acid (40.1 mg, 0.232 mmol), bis(triphenylphosphine)palladium(II) chloride (16.26 mg, 0.023 mmol) and potassium carbonate (112 mg, 0.811 mmol) and the mixture heated at 100° C. for 1 h using a microwave reactor. The mixture was then filtered through celite, washing with ethyl acetate (30 mL) and the filtrate evaporated to dryness. The residue was then purified by MDAP (acidic conditions), to afford the title compound (41.45 mg). LCMS (A) m/z: 480 [M+1]+, Rt 1.13 min (acidic).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH:3]([CH2:7][N:8]2[C:13]3[CH:14]=[CH:15][NH:16][C:12]=3[C:11](=[O:17])[NH:10][C:9]2=[S:18])[CH2:2]1.[CH:19](O)=O.[BH3-]C#N.[Na+]>CO>[CH3:19][N:1]1[CH2:6][CH2:5][CH2:4][CH:3]([CH2:7][N:8]2[C:13]3[CH:14]=[CH:15][NH:16][C:12]=3[C:11](=[O:17])[NH:10][C:9]2=[S:18])[CH2:2]1
Reactant: O=c1[nH]c(=S)n(CC2CCCNC2)c2cc[nH]c12
Reactant: O=CO
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CN1CCCC(Cn2c(=S)[nH]c(=O)c3[nH]ccc32)C1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 22.6 %

Procedure:
1-Piperidin-3-ylmethyl-2-thioxo-1,2,3,5-tetrahydro-pyrrolo[3,2-d]pyrimidin-4-one (Example 7) (0.092 g, 0.35 mmol) was dissolved in methanol (2 mL) and formic acid (37% aq., 0.059 mL, 0.7 mmol) was added. After 5 minutes of stirring at r.t. a precipitate had formed. NaCNBH3 (0.026 g, 0.42 mmol) was added and the mixture was stirred at r.t. for 1 h. The solvent was removed in vacuo and the residual solid was purified by preparative HPLC, obtaining the title compound (0.022 g, 22%) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]([N:11]1[CH2:16][CH2:15][NH:14][C:13]2[N:17]=[CH:18][C:19](I)=[CH:20][C:12]1=2)=[O:10].[CH3:22][N:23]1[CH2:28][CH2:27][N:26]([C:29]([C:31]2[CH:36]=[CH:35][C:34](B3OC(C)(C)C(C)(C)O3)=[CH:33][CH:32]=2)=[O:30])[CH2:25][CH2:24]1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]([N:11]1[CH2:16][CH2:15][NH:14][C:13]2[N:17]=[CH:18][C:19]([C:34]3[CH:33]=[CH:32][C:31]([C:29]([N:26]4[CH2:27][CH2:28][N:23]([CH3:22])[CH2:24][CH2:25]4)=[O:30])=[CH:36][CH:35]=3)=[CH:20][C:12]1=2)=[O:10]
Reactant: O=C(c1cc(F)ccc1F)N1CCNc2ncc(I)cc21
Reactant: CN1CCN(C(=O)c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Product: CN1CCN(C(=O)c2ccc(-c3cnc4c(c3)N(C(=O)c3cc(F)ccc3F)CCN4)cc2)CC1
Yield: 36 %

Procedure:
(2,5-Difluorophenyl)-(7-iodo-3,4-dihydro-2H-pyrido[2,3-b]pyrazin-1-yl)methanone (35 mg) was reacted with (4-methylpiperazin-1-yl)-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)phenyl]methanone as in General Procedure 4A to give the title compound as a light yellow solid (36% yield). M.p. 201-203° C., LCMS: m/z=478.10 (M+H+), 1H-NMR (CDCl3, 400 MHz) δ 2.32 (s, 3H), 2.33-2.52 (m, 4H), 3.40-3.85 (m, 8H), 5.31 (s, 1H), 6.70-7.05 (m, 3H), 7.15 (s, 1H), 7.24-7.45 (m, 4H), 8.09 (s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([OH:12])=[O:11])=[CH:5][CH:4]=1.[Li+].[CH3:14][Si]([N-][Si](C)(C)C)(C)C.[C:23]([C:25]1[CH:33]=[CH:32][C:28]([C:29](Cl)=[O:30])=[CH:27][C:26]=1[F:34])#[N:24].[NH4+].[Cl-]>C1COCC1>[CH3:14][O:11][C:10](=[O:12])[CH:9]([C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=1)[C:29]([C:28]1[CH:32]=[CH:33][C:25]([C:23]#[N:24])=[C:26]([F:34])[CH:27]=1)=[O:30]
Reactant: N#Cc1ccc(C(=O)Cl)cc1F
Reactant: COc1ccc(CC(=O)O)cc1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [Li+]
Agent: [NH4+]
Solvent: C1CCOC1
Product: COC(=O)C(C(=O)c1ccc(C#N)c(F)c1)c1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 45.8 %

Procedure:
To a solution of (4-methoxy-phenyl)-acetic acid (2.18 g, 12.12 mmol) in THF (20 mL) was added LiHMDS (18.2 mL, 18.18 mmol) at −78° C. and the mixture was stirred for 30 min. A solution of 4-cyano-3-fluoro-benzoyl chloride (2.2 g, 12 mmol) in THF was added dropwise at −78° C.; and the reaction mixture was allowed to warm up to RT and stirred at overnight. Aqueous NH4Cl was added and the aqueous was extracted with EA (3×). The combined organics were concentrated in vacuo and the residue was purified by silica column chrmatography (1:5, EA: PE) to give 1.8 g (45%) of the title compound. [M+H] Calc'd for C18H14FNO4, 328. Found, 328.
Reaction SMILES: [CH3:1][C:2](=[O:5])[CH2:3][CH3:4].[CH3:6][C:7]([O:14]O)([CH3:13])[CH2:8][C:9]([CH3:12])([CH3:11])[CH3:10].S(=O)(=O)(O)O.[O:21]=[O:22]>CCCCC>[C:7]([O:21][O:22][C:2]([O:5][O:14][C:7]([CH2:8][C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:13])[CH3:6])([CH2:3][CH3:4])[CH3:1])([CH2:8][C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:13])[CH3:6]
Reactant: CC(C)(C)CC(C)(C)OO
Reactant: CCC(C)=O
Reactant: O=O
Agent: O=S(=O)(O)O
Solvent: CCCCC
Product: CCC(C)(OOC(C)(C)CC(C)(C)C)OOC(C)(C)CC(C)(C)C
Temperature: 0 °C
Reaction time: 4 h
Yield: 54.2 %

Procedure:
To a jacketed reactor was charged 8.36g. (0.116 mole) of 2-butanone, 38.0g. (0.232 mole) of 1,1,3,3-tetramethylbutyl hydroperoxide (89.7% assay) and 100 ml. of pentane. To the vigorously stirred mixture at 0°C was added 17.2g. of 77% sulfuric acid over a period of 15 minutes and the mixture was allowed to stir at 0°C for 4 hours. The product was worked up as in Example I and 23.8g. (59.5% of theory, uncorr.) of liquid was obtained which had an active oxygen content of 8.41% (theory, 9.25%). Hence, the assay of the product was 91.0% and the corrected yield was 54.2%. An infrared spectrum of the product showed no OH or C=O bands but showed a strong and broad OO band centered at 875 cm-1.
Reaction SMILES: Br[C:2]1[N:7]2[CH:8]=[CH:9][N:10]=[C:6]2[CH:5]=[CH:4][CH:3]=1.BrCC.[C:14](OCC)(=[O:20])[C:15]([O:17][CH2:18][CH3:19])=[O:16]>O1CCCC1>[CH2:18]([O:17][C:15](=[O:16])[C:14]([C:2]1[N:7]2[CH:8]=[CH:9][N:10]=[C:6]2[CH:5]=[CH:4][CH:3]=1)=[O:20])[CH3:19]
Reactant: CCOC(=O)C(=O)OCC
Reactant: Brc1cccc2nccn12
Solvent: CCBr
Solvent: C1CCOC1
Product: CCOC(=O)C(=O)c1cccc2nccn12
Temperature: -15 °C
Reaction time: 0.5 h

Procedure:
Add Mg turnings (0.25 g, 9.95 mmol) to a solution of 5-Bromoimidazo[1,2-a]pyridine (1.5 g, 7.65 mmol) in tetrahydrofuran (20 ml). Heat the reaction to 60° C. and add bromoethane (1.2 ml, 11.1 mmol). Reflux for another 0.5 hours, cool and cannula dropwise into a solution of diethyl oxalate (5 ml) in tetrahydrofuran (5 ml) at −15° C. Stir at −15° C. for 0.5 hours and at room temperature for 0.5 hours. Quench the reaction by adding pH 7 buffer, extract into ethyl acetate, wash with saturated sodium chloride, dry over magnesium sulfate, and concentrate under reduced pressure. Purification by flash chromatography, eluting with ethyl acetate:hexane:methanol gradient gives the title compound as a light brown oil.